Obstetric and neonatal outcomes in pregnant women with idiopathic polyhydramnios: a systematic review and meta-analysis

Although the assessment of the amniotic fluid volume in pregnancy is part of the fetal wellbeing surveillance, the impact of idiopathic polyhydramnios (IP) on maternal and perinatal outcomes in unknown. The aim of this meta-analysis was to investigate the association of IP with different maternal and perinatal outcomes. We screened five electronic databases until December 2023 and performed data extraction and quality assessment using ROBINS-E in duplicates. Pooled risk ratios and 95% confidence intervals (95% CI) were calculated with a random effects model. 38 studies were included. Patients with IP were at increased risk of perinatal complications including preterm delivery (RR 1.96, 95% CI 1.35–2.86; I2 = 92%), placental abruption (RR 3.20, 95% CI 2.20–4.65; I2 = 2%), delivery via caesarean section (RR 1.60, 95% CI 1.39–1.84; I2 = 95%) and postpartum haemorrhage (RR 1.98, 95% CI 1.22–3.22; I2 = 84%). Similarly, IP was associated with increased risk of adverse perinatal outcomes including low APGAR score (RR 3.0, 95% CI 1.23–7.35; I2 = 95%), stillbirth (RR 4.75, 95% CI 2.54–8.86; I2 = 9%) and perinatal mortality (RR 4.75, 95% CI 2.67–8.48; I2 = 37%). This meta-analysis suggests that pregnant women with IP may be at increased risk of perinatal complications and adverse neonatal outcomes. However, data remains inconclusive considering the low quality and high heterogeneity of included studies. PROSPERO registration number: CRD42022359944.


Data extraction and risk of bias
Data were independently extracted by KSK and GZ in pre-specified forms.Discrepancies were discussed and resolved by KKT and MS.Risk of bias (RoB) was assessed by two authors independently (KSK and KKT) using ROBINS-E tool (Risk Of Bias In Non-randomised Studies-of Exposures) for observational studies.
The GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach was used to assess the quality of evidence of the main outcomes.The assessment was based on five parameters: risk of bias, inconsistency (known also as heterogeneity) between studies, indirectness, imprecision (risk of random errors), and publication bias.The evidence for each item was rated as high, moderate, low, or very low.

Statistical analysis
We combined study effect sizes using risk ratios (RR) along with corresponding 95% confidence intervals (95% CIs) under the random-effects meta-analysis model and the inverse variance method.Statistical heterogeneity was assessed by using the x 2 test (p < 0.10 to indicate statistically significant heterogeneity) and I 2 (to quantify the degree of heterogeneity).I 2 from 30 to 49% was defined as moderate heterogeneity and 50% or more was defined as high heterogeneity for the data 8 .The Der Simonian and Laird estimator was used to estimate the between-study variance.Visual inspection of the funnel plot was used to assess for publication bias when more than ten studies were available for each outcome.
To explore the possible sources of heterogeneity, we performed predefined sensitivity analyses for every outcome restricting to: studies with moderate or low risk of bias.Given that our meta-analysis examined rare events and due to possible publication bias, we also performed fixed-effects (FE) meta-analysis using the Mantel-Haenszel method; this approach provides more reliable estimates of the summary effect, at the cost of ignoring heterogeneity.
We further conducted a series of subgroup analyses to explore sources of heterogeneity and differences in summary estimates according to: continent (Europe vs Americas vs Asia), mean maternal age (> 30 years vs ≤ 30 years), study design (retrospective vs prospective), definition of idiopathic polyhydramnios (DVP vs AFI vs mixed criteria), year of study (> 2010 vs ≤ 2010), mean birth weight (< 3 kg vs 3-3.5 kg vs > 3.5 kg) and gestational week at diagnosis (> 26 weeks vs ≤ 26 weeks).
The meta-analysis was performed using RevMan (Review Manager) Web in the online platform provided for Cochrane intervention reviews (RevMan, Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration, 2008).

Risk of bias
The majority of the included studies (36/38) were classified as of low or moderate risk of bias with adequate overall design (ROBINS-E tool).However, some concerns were identified related to the exposure window and selection of participants (26/38) as well as to the selection of reported results (2/38).Additionally, two studies (2/38) were characterised as of high risk of bias due to the potential presence of uncontrolled confounding factors (supplementary material).

Antenatal complications
Our analysis showed that women with idiopathic polyhydramnios were at increased risk of delivering preterm compared to women with normal AFV (15 1, Fig. 2a).Confidence in this meta-analysis was low according to GRADE due to the presence of inconsistency as a result of high heterogeneity and non-overlapping confidence intervals.

Overview
The findings of this meta-analysis suggest that pregnant women with idiopathic polyhydramnios may be at increased risk of perinatal complications including preterm delivery, labour induction, placental abruption, shoulder dystocia, delivery via caesarean section, and postpartum haemorrhage.Additionally, our analysis showed that idiopathic polyhydramnios may potentially increase the risk of adverse perinatal outcomes including low 1-min and 5-min APGAR scores, stillbirth and perinatal mortality.These results should be interpreted with

Findings in the context of the literature
Although pregnancies complicated by idiopathic polyhydramnios are characterised as high risk 42 , there is still no agreement in regards to specific complications associated with the condition.As a result, reports in the literature suggest that antenatal fetal surveillance is not required in cases of idiopathic polyhydramnios 1 .The included studies have used either AFI or DVP.Nevertheless, the fact that the available studies did not provide data according to polyhydramnios severity and their results are inconsistent demonstrates that the condition deserves further study as a potential risk factor for adverse perinatal outcomes.www.nature.com/scientificreports/One previous meta-analysis attempted to synthetise the evidence to date and suggested induction of labour at 39 weeks in pregnancies complicated by idiopathic polyhydramnios 46 .Our findings on the summary estimates are in agreement with this study, which, however, only included a fraction of the published literature, failed to include grey literature and unpublished data in the search and implemented exclusion criteria that affected the final number of studies with potentially relevant data.Additionally the presence of significant inconsistency was not explored and was not associated with the overall quality of the data.GRADE assessment was not performed, whilst the risk of bias tool used (Newcastle-Ottawa Scale) is not recommended by the Cochrane Library 46 .
From a pathophysiological point of view, increased AFV can cause uterine overdistention which can potentially explain the increased risk of preterm labour, placental abruption and PPH as the uterus becomes less responsive to oxytocin, leading to uterine atony 26 .Uterine overdistention and increased intrauterine pressure could also lead to a degree of 'placental insufficiency' and this could explain the altered feto-placental Doppler velocimetry seen in patients diagnosed with idiopathic polyhydramnios 34,47 .This putative mechanism could represent a possible link between idiopathic polyhydramnios and adverse neonatal outcomes including low APGAR scores and perinatal mortality.

Strengths and limitations
To our knowledge, this is the most comprehensive systematic review and meta-analysis to report on the effect of idiopathic polyhydramnios on perinatal outcomes with thorough methodological assessment of risk of bias, heterogeneity, and appropriate data synthesis.
We used a reliable risk of bias tool (ROBINS-E) to explore the quality of the included studies.We further explored the possibility of publication bias in our meta-analysis using the assessment of funnel plot symmetry.We performed a thorough assessment of the grey literature and we also assessed our findings using both fixed and random effects meta-analyses, as well as using a series of subgroup and sensitivity analyses that controlled for risk of bias, study design, birth weight, maternal age, year of publication, timing of diagnosis etc.
However, the findings should be interpreted with caution.The majority of the published literature comes from observational studies at risk of bias.These observational studies were of moderate quality based on the ROBINS-E tool and only a small fraction of them provided adjusted data.The moderate quality of the included articles should be attributed, at least partially, to the presence of confounders, the differences between intervention and control groups, especially regarding birthweight, and the suboptimal selection of participants.Specifically, the mean age of participants was not provided in most of the studies and age differences may impact on the outcomes that we investigated.Moreover, the high diversity amongst studies with regards to definition of exposure, definition of outcomes and length of follow-up could also influence the accuracy of the summary effect estimates.Additionally, heterogeneity related to intrapartum care and management should be also mentioned as a potential source of indication bias.An example includes epidural analgesia which can be affected by patients' preferences.Regarding preterm labour, the differentiation between spontaneous and induced was not feasible due to lack of data from the included studies.Lastly, data regarding the mean gestational age of delivery was not provided by the included studies and as a result we were not able to perform additional analyses based on this confounder.The observed heterogeneity in several meta-analyses was high, as indicated by the I 2 estimates and the wide non-overlapping confidence intervals, highlighting the uncertainty around the observed effect estimates.While specific subgroup and sensitivity analyses showed consistent results and were able to reduce this heterogeneity to some extent, the number of included studies in these subgroups was low.Additionally, the difference in effect estimates between the random and fixed effect models also indicates the potential presence of publication bias.The assessment of publication bias was restricted by the limited number of studies for some comparisons further highlighting the need for prospectively designed studies with long follow up periods.Finally, the quality of evidence and the certainty related to our results ranged from very low to low as assessed by GRADE due to the observational nature of the included studies and the presence of inconsistency.

Conclusions
The findings of this meta-analysis suggest that pregnant women with idiopathic polyhydramnios may be at increased risk of perinatal complications and adverse neonatal outcomes.However, the quality of evidence for the majority of the studied outcomes ranged from very low to low; as such, the data remain inconclusive.Largescale high-quality prospectively designed studies are required to investigate more robustly the effect of idiopathic polyhydramnios on pregnancy outcomes and optimal time of delivery.Until further data is available, antenatal fetal surveillance could be considered in pregnancies complicated by this condition.